Thermal Cα–C6 Cyclization of Enediynes

Abstract

Canonical thermal cycloaromatizations (Bergman, C¹–C⁶; Myers-Saito, C²–C⁷; Schmittel, C²–C⁶; Schreiner-Pascal, C¹–C⁵) are limited to the formation of five- or six-membered rings, while the formation of larger rings from enediyne (or enyne-allenes) has no precedent experimental exploration. Herein, we present a novel thermal cyclization of enediyne, leading to the formation of a stable seven-membered cyclization product. The structure of this product was elucidated by using NMR and single-crystal X-ray diffraction techniques. The presence of a maleic hydrazide moiety is postulated to facilitate the proton transfer, resulting in the rearrangement of enediyne to enyne-allene, culminating in ring closure through C^α–C⁶ cyclization. The reaction mechanism was further explored by using density functional theory (DFT), revealing a low activation barrier for the C^α–C⁶ cyclization at 19.6 kcal/mol. The newly formed seven-membered ring exhibits strong Möbius aromaticity, as confirmed by calculations of the nucleus-independent chemical shift (NICS) and anisotropy of the induced current density (ACID). In the subsequent reaction, the fusion of the oxazolidin-2-one ring and the elimination of the isobutene molecule release a significant amount of energy, further driving the formation of the final product.